Therapeutic compounds

a technology of compounds and compounds, applied in the field of therapeutic compounds, can solve the problems of increased cancer risk, metastasis, relapse, patient mortality,

Active Publication Date: 2016-03-29
RGT UNIV OF MINNESOTA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Malignant tumors contain aerobic and hypoxic regions and intratumoral hypoxia increases the risk of cancer advancement, and metastasis.
Tumor hypoxia leads to treatment failure, relapse and patient mortality as these cells are generally resistant to standard chemo- and radiation therapy.
Under hypoxic conditions, cancer cells upregulate glucose transporters and consume large quantities of glucose.
Targeted inhibition of MCT4 will lead to lactic acidosis and consequent death of hypoxic cells, while MCT1 inhibition will cause aerobic cancer cells to consume glucose instead of lactate, thus resulting in further stress and death of hypoxic cancer cells.
The rate of short term graft survival has been improved by current immunosuppressants, however in the past two decades there has been no improvement in the abilities of agents to promote long term graft survival.
This in turn decreases glycolytic flux effectively limiting the proliferation of new lymphocytes.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compounds 4-12 (Table I)

[0195]

[0196]To a solution of the substituted benzaldehyde (10 mmol) in 20 ml acetonitrile or ethanol, was added cyanoacetic acid (15 mmol) and piperidine (10 mmol) and refluxed for 3-8 h at 80° C. Upon the completion of the reaction, the above solution was poured into a mixture of 3M HCl (10 mL) in ice. The solution was stirred for 10 to 15 minutes and the solid was filtered using Buchner funnel. The solid was washed with water and acetonitrile. The pure compound was obtained upon recrystallization.

[0197]

TABLE 2ElementalElementalCompoundCalculatedObservedYieldNumberCompoundC %H %N %C %H %N %(%) 471.978.059.3371.838.389.3565 573.148.598.5372.618.378.1670 674.129.057.8674.189.997.7468 771.626.0110.4470.986.6611.3660 872.724.5810.670.624.710.2862 971.978.059.3371.488.499.23611078.245.477.6077.305.337.88721169.415.8211.5668.755.5011.20681270.296.2910.9370.516.4511.0167

example 2

Synthesis of Compounds 13-21 (Table 3)

[0198]

[0199]To a solution of the substituted o-methoxy-benzaldehyde (10 mmol) in 20 ml acetonitrile or ethanol was added cyanoacetic acid (15 mmol) and piperidine (10 mmol) and refluxed for 10-20 h at 80° C. Upon the completion of the reaction, the above solution was poured into a mixture of 3 M HCl (10 mL) in ice. The solution was stirred for 10 to 15 minutes and the solid was filtered using Buchner funnel. The solid was washed with water and acetonitrile and the pure compound was obtained upon recrystallization.

[0200]

TABLE 3ElementalElementalCompoundCalculatedObservedYieldNumberCompoundC %H %N %C %H %N %(%)1367.537.339.2667.117.359.14621469.067.938.4870.017.668.56601570.368.447.8170.518.607.92741668.446.089.3968.596.129.48701769.384.799.5269.894.999.78661869.067.938.4868.957.578.66581975.365.577.0375.795.867.34622074.584.907.5674.124.477.82662166.165.9210.2966.365.8610.3168

example 3

Synthesis of Compounds 22-29 (Table 4)

[0201]

[0202]To a solution of substituted o-hydroxy-benzaldehyde (10 mmol) in 20 ml ethanol, was added diethyl malonate (20 mmol) and piperidine (13 mmol) and refluxed for 8-12 h at 80° C. Upon the completion of the reaction, the above solution was evaporated and further refluxed in 10 ml of 10% NaOH solution. The reaction was quenched with 3M HCl and worked up with ethyl acetate. The compound was purified by column chromatography (eluted with 100% ethyl acetate) and recrystallized.

[0203]

TABLE 4ElementalElementalCompoundCalculatedObservedYieldNumberCompoundC %H %N %C %H %N %(%)2266.426.624.8466.546.764.91502367.365.304.9167.385.194.98642468.323.944.9868.393.974.86532574.794.973.6374.874.563.84582664.865.055.4064.214.875.12592768.414.073.3268.664.343.38552863.453.773.0863.553.842.97572965.964.052.9665.873.873.0855

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Abstract

The invention provides compounds of formula (I) or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula (I), processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula (I) and therapeutic methods for treating cancer or treating autoimmune diseases or preventing transplant rejection using compounds of formula (I).

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 61 / 589,090 that was filed on 20 Jan. 2012.BACKGROUND OF THE INVENTION[0002]Monocarboxylate Transporters (MCTs) are members of the solute carrier 16 (SLC16) gene family. In mammalian species there are 14 known MCT isoforms and only four (MCT-1, -2, -3, -4) have been demonstrated to perform proton-linked transport of monocarboxylates such as lactate, pyruvate, butyrate, and ketone bodies.[0003]Malignant tumors contain aerobic and hypoxic regions and intratumoral hypoxia increases the risk of cancer advancement, and metastasis. Tumor hypoxia leads to treatment failure, relapse and patient mortality as these cells are generally resistant to standard chemo- and radiation therapy. In regions of hypoxia, cancer cells metabolize glucose into lactate, whereas nearby aerobic cancer cells take up this lactate via the mono-carboxylate transporter 1 (MCT1) for oxidative phosphorylation. MCT1 expression...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D311/02C07D407/14C07D311/12C07D207/09C07C255/63C07D295/155C07C255/41C07D405/04
CPCC07D405/04C07C255/41C07C255/63C07D207/09C07D295/155C07D311/12C07D407/14C07D311/16
Inventor MEREDDY, VENKATRAM, R.DREWES, LESTER, R.ALAM, MOHAMMED, ABRARJONNALAGADDA, SRAVAN, K.GURRAPU, SHIRISHA
Owner RGT UNIV OF MINNESOTA
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